Aggregation of α-synuclein is kinetically controlled by intramolecular diffusion
Aggregation of α-synuclein is kinetically controlled by intramolecular diffusion
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DOI：
10.1073/pnas.1109526109
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发表时间：
2012-02-14
影响因子：
11.1
通讯作者：
Lapidus, Lisa J.
中科院分区：
文献类型：
--
作者：
Ahmad, Basir;Chen, Yujie;Lapidus, Lisa J.
我们假设无序蛋白质（例如α-突触核蛋白）聚集的第一步是由主链重构速率控制的。当重配置快时，双分子缔合不稳定，但当重配置慢时，缔合更稳定，随后的聚集更快。为了研究这一假设，我们测量了 α-突触核蛋白（一种与帕金森病有关的蛋白质）在加速或减速聚集的溶剂条件下的分子内扩散速率。使用色氨酸-半胱氨酸 (Trp-Cys) 猝灭方法，在沿链长的四个不同环中测量分子内接触速率。这种本质上无序的蛋白质在低温、中性 pH 值下聚集缓慢时高度扩散，而在高温或低 pH 值聚集快速时压缩和扩散更慢。随着疾病突变 A30P，扩散也会减慢。这项工作为α-突触核蛋白聚集途径的最早步骤提供了独特的见解，并为开发可在初始阶段阻止聚集的药物提供基础。
We hypothesize that the first step of aggregation of disordered proteins, such as alpha-synuclein, is controlled by the rate of backbone reconfiguration. When reconfiguration is fast, bimolecular association is not stable, but as reconfiguration slows, association is more stable and subsequent aggregation is faster. To investigate this hypothesis, we have measured the rate of intramolecular diffusion in alpha-synuclein, a protein involved in Parkinson's disease, under solvent conditions that accelerate or decelerate aggregation. Using the method of tryptophan-cysteine (Trp-Cys) quenching, the rate of intramolecular contact is measured in four different loops along the chain length. This intrinsically disordered protein is highly diffusive at low temperature at neutral pH, when aggregation is slow, and compacts and diffuses more slowly at high temperature or low pH, when aggregation is rapid. Diffusion also slows with the disease mutation A30P. This work provides unique insights into the earliest steps of alpha-synuclein aggregation pathway and should provide the basis for the development of drugs that can prevent aggregation at the initial stage.